Action Points

The adenosine 2A (A2A) receptor antagonist preladenant didn't reduce "off" time in Parkinson's in two trials, but that may have been due to poor trial design.

Note that preladenant was well tolerated, with the most common adverse event being constipation, occurring in 6% to 8% of those in the drug groups compared with 1% to 3% for those on placebo.

The adenosine 2A (A2A) receptor antagonist preladenant didn't reduce "off" time in Parkinson's in two trials, but that may have been due to poor trial design and management at individual sites, researchers reported.

"Because the active control (rasagiline) also failed to demonstrate a significant reduction in off time, it is not possible to determine from these results whether they represent a finding of inefficacy for preladenant, or are related to issues of study design or conduct," the researchers wrote.

Three adenosine 2A receptor antagonists -- istradefylline, preladenant, and tozadenant -- are in development for Parkinson's disease, and this is the second phase III trial with disappointing results with this class of agents.

All three drugs yielded positive results in phase II trials, but istradefylline had mixed results in phase III, preladenant just failed its two phase III trials, and tozadenant is still in phase III development.

The drugs provide a nondopaminergic target for Parkinson's and are thought to work by reducing overactivity of striatopallidial output neurons. They're intended to be an add-on to levodopa in Parkinson's patients who have motor fluctuations.

Hauser and colleagues conducted the two 12-week randomized controlled trials in several international centers, with moderate-to-severe Parkinson's patients who were already taking levodopa.

The first trial enrolled 778 patients who were randomized to an add-on of placebo, rasagiline, or one of three doses of preladenant twice daily: 2 mg, 5 mg, or 10 mg.

In the second trial, 476 patients were randomized to placebo or to one of two twice-daily doses of preladenant: 2 mg or 5 mg.

The primary outcome in both studies was the change in "off" time from baseline to week 12.

In the first trial, they found that neither preladenant nor rasagiline was superior to placebo in reducing "off" time during that time period. Here are the reductions in "off" time compared with placebo; none of which amount to a significant difference:

2 mg: -0.10 hour (95% CI −0.69 to 0.46 hour)

5 mg: -0.20 hour (95% CI −0.75 to 0.41 hour)

10 mg: -0.00 hour (95% CI −0.62 to 0.53 hour)

Rasagiline mesylate 1 mg/d: -0.30 hour (95% CI −0.90 to 0.26 hour)

The percentage of responders with at least a 30% decrease in "off" time at week 12 was similar among all three groups, ranging from 31% to 36%, the researchers reported.

Similarly, in the second trial, preladenant wasn't superior to placebo in reducing "off" time, with no significant differences compared with placebo:

2 mg: -0.20 hour (95% CI −0.72 to 0.35 hour)

5 mg: -0.30 hour (95% CI −0.86 to 0.21 hour)

The mean increases in "on" time without dyskinesia at week 12 were similar across groups, the researchers added.

They noted, however, that preladenant was well tolerated, with the most common adverse event being constipation, occurring in 6% to 8% of those in the drug groups compared with 1% to 3% for those on placebo.

They also noted that there was one suicide in the second trial -- a self-inflicted gunshot wound to the chest -- which was considered possibly related to the study drug by the investigator.

Hauser and colleagues said the studies offer several lessons for trial design in further development of these drugs, which they highlight in a boxed section of the article.

A post-hoc analysis of the first trial revealed a large placebo effect at sites in Turkey, India, and Latin America, prompting a need for careful choice of sites and regions, as well as specialized training to mitigate placebo response, they wrote.

A second lesson is that more patients are not always better, they said. In both trials, enrollment sped up significantly as the trial went on, which "could potentially have degraded the quality of patients that sites were enrolling," they wrote.

"We hypothesize that sites enroll their most ideal patients first and then may 'scrape the bottom of the barrel' to find additional patients to enroll," they wrote.

Having ideal patients is important, they said, because the studies rely on patient diaries. Patients have to be taught to recognize motor states and complete their diary in a timely and acute manner.

"It seems likely that these requirements would be easiest to accomplish at a small number of expert sites with a successful clinical trial track record and a large population of well-known patients from which to draw, which appears to be the case for phase II trials but becomes more difficult in phase III trials, when more sites and more participants are required," they wrote.

Their solution to this challenge: avoid having to enroll more patients than necessary.

The studies were funded by Merck. Some study authors are employees of Merck.

More in Neurology

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.